Our broad term objective is two-fold: to understand how extracellular RNA (exRNA) modulates the phenotype of normal cells in the tumor environment and to generate new experimental modalities that can elucidate mechanisms underlying this form of communication among cells. Specifically we will focus on understanding how exRNA released from glioblastoma cells modulates the phenotype of normal cells in the vicinity of the tumor. Our overall specific aims will encompass:
Aim 1 - Elucidation of basic molecular and cellular mechanisms of exRNA biogenesis by GBM cells, and uptake and function in normal brain cells, using existing and emerging technologies to manipulate these processes.
Aim 2 - Full characterization of the exRNA content and intracellular RNA content of human GBM cells, as well as the intracellular RNA content of normal brain cells, and evaluation of functional transfer of exRNAs from GBM cells to brain cells in culture and in GBM mouse brain models.
Aim 3 - Evaluation of transfer and fate of exRNA in brain cells, including visualizing RNA transfer in EVs, monitoring mRNA translation and miRNA functions, determining possible genomic integration of transposable elements/oncogenes, and evaluation of effects of non-coding exRNAs on status of genome methylation.
Aim 4 - Description of the dependence of exRNA cargo composition, formation and release dynamics as a function of GBM genotype, including activation of EGFR and PDGFRa signaling pathways, the two most common genetic events in human GBM tumors, as well as changes in GBM exRNA in response to radiation and drug treatment.
Aim 5 - Development of regulators and reporters of exRNA release and uptake by tailoring fluorescent and other visual labels, vectors, mouse models and reagents for broad applications in monitoring exRNA release, uptake and function in culture and in vivo.
These aims will be supported by a shared imaging core carrying our intravital imaging of extracellular vesicles and their interaction with endogenous cells in the brain.

Public Health Relevance

An insidious aspect of cancer is its ability to subvert normal cells to promote tumor growth. This process is believed to be mediated in large part through RNA vehicles released by tumor cells and taken up by normal cells. Understanding this subversive mechanism will allow development of novel therapeutic interventions to curtail cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZRG1-OBT-S (50))
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Howcroft, Thomas K
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Massachusetts General Hospital
United States
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